In virtually any organism, immunity to infections is contributed by evolutionary conserved peptides with a striking ability to eradicate microbial organisms. Hence, named host defense peptides, or more frequently antimicrobial peptides (AMPs). AMPs are secreted as inactive precursors and proteolytically activated into potent antimicrobial peptides by serine proteases. The current dogma is that AMPs act to destabilize the cell membrane of microorganisms through electrostatic interactions between the cationic AMPs and the anionic microbial membrane (Zasloff, M., Antimicrobial peptides of multicellular organisms. Nature, 2002. 415(6870): p. 389-95). The electrostatic interactions allow these peptides to permeabilize the membrane lipid bilayer, thereby leading to the formation of membrane pores, cell depolarization, leakage of intracellular contents, and ultimately cell death (Brogden, K. A., Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol, 2005. 3(3): p. 238-50). These proteins have consequently been considered as potential antibiotics for use in prevention or treatment of infections in humans. Unfortunately, the positive charge of these proteins also enables a range of unwanted effects on human cells. Most prominently, AMP such as ovispirin lyse human erythrocytes, whereas LL-37 has been shown to destroy human cells, including leukocytes, through destabilization of the cellular membrane (S. H. Christiansen, K. Juul-Madsen, B. Vad, M. Behrens, B. Jalilian, J. S. Pedersen, D. Otzen and and T. Vorup-Jensen et al., 2014, in preparation,).
While LL-37 and other similar peptides, in principal, could serve as agents useful for antimicrobial treatment in humans, conflicting observations suggest that the ability to destroy human cells hinders efficient clinical application (Dorosz, J., et al., Membrane interactions of novicidin, a novel antimicrobial peptide: phosphatidylglycerol promotes bilayer insertion. J Phys Chem B, 2010. 114(34): p. 11053-60). Furthermore, others have cautioned that the treatment with manufactured, but biologically similar AMPs possibly could induce microbial resistance to evolutionarily conserved host defense peptides, such as LL-37 (Habets, M. G. and M. A. Brockhurst, Therapeutic antimicrobial peptides may compromise natural immunity. Biol Lett, 2012. 8(3): p. 416-8).
Moreover, an increasing antimicrobial resistance to conventional antibiotics threatens an effective prevention and treatment of microbial infections. Thus, there is a need for identifying new and safe drugs that can be used in the treatment of microbial infections, such as bacterial infections.